Our findings reveal that high expression of LGALS9 suppresses T cell function, fosters a strongly immunosuppressive tumor microenvironment, and is associated with chemotherapy resistance, ineffective immunotherapy, and poor prognosis. LGALS9 may serve as a biomarker for predicting immunotherapy response. This knowledge has the potential to facilitate early diagnosis, precise molecular typing, accurate prognosis evaluation, and the development of personalized treatment strategies that can overcome tumor drug resistance and improve patient outcomes.